1. Autoregulation of renal blood flow and GFR is a mechanism that describes a direct relationship between arterial blood pressure and glomerular vascular resistance. It has been recognized that this mechanism is of primary importance in preventing the transmission of the high systemic pressure into the glomerulum thereby protecting the glomerular capillaries against pressure injury. Autoregulation is the result of at least two distinct mechanisms, a general myogenic response to wall tension and a kidneyspecific effect mediated by the tubuloglomerular feedback system. NKCC1 is a furosemidesensitive Na,K,2Cl cotransporter that is expressed in secretory epithelia, but is also found in most blood vessels including in the afferent renal arteriole. Because of previous evidence implicating NKCC1 in the control of glomerular function and renin secretion we have studied its participation in renal autoregulation by comparing autoregulatory efficiencies in wild type and NKCC1-deficient mice using both time and frequency domain analyses. Arterial blood pressure measured via a catheter in the femoral artery and renal blood flow (RBF) measured with a perivascular flowmeter module were recorded at 100 Hz over 1520 interventionfree minutes. Transfer and coherence functions were evaluated and compared between wild type and NKCC1 mice. Transfer function gain values were evaluated in the frequency ranges known to represent myogenic (0.20.5 Hz) and tubuloglomerular feedback (TGF) frequency ranges (0.050.1 Hz). Both myogenic and TGF transfer function gain values were higher in the NKCC1 than the wild type mice (myogenic: 0.27 vs. 0.24, p<0.04; TGF: 0.05 vs. 0.036, p<0.014). The coherence function values were also higher in both myogenic and TGF frequency ranges for NKCC1 than wild type mice. Analysis of the speed of resistance adjustment following a step increase in arterial blood pressure confirmed that both myogenic and TGFdependent resistance changes are compromised in the absence of NKCC1. A marked attenuation of TGF responsiveness in NKCC1 deficienct mice was directly demonstrated by micropuncture methods. We conclude that NKCC1 is of critical importance in permitting rapid and precise resistance adjustments in the face of changing arterial pressure.[unreadable] 2. Adenosine in the kidney mediates the vascular response elicited by changes in NaCl concentration in the macula densa region of the nephron, thereby serving as an important regulator of GFR. Impairment of tubuloglomerular feedback (TGF) regulation in ecto5nucleotidase (CD73) deficient mice suggested extracellular generation of adenosine from AMP as the source for juxtaglomerular adenosine. To determine whether the AMP precursors ADP and ATP are also involved, we studied TGF regulation in mice with targeted deletion of ENTPD1CD39. ENTPDaseCD39 is an ectoenzyme that catalyses the hydrolysis of ATP and ADP to AMP. Maximum TGF responses of glomerular capillary pressure in CD39deficient mice were markedly reduced compared to wild type animals. The response to an elevation of flow from 0 to 30 nlmin was a decrease of glomerular capillary pressure by 3.3 plusminus 1.0 mm Hg compared to a decrease of 9.4 plusminus 1.3 mm Hg in wild type mice. Ambient GFR in CD39, as determined by FITCinulin disappearance kinetics in conscious mice, was not different from wild types averaging 1068 in CD39 (n6) and 1116 microlmin100g body weight in CD39 mice (n11; p0.7). Plasma renin concentration (ng Ang Iml hr) averaged 555 in wild type and 451 in CD39 mice (n6, p0.38). Our data indicate that ATP and ADP hydrolysis via ENTPDase1CD39 is part of an extracellular dephosphorylation cascade that leads to the generation of adenosine in the juxtaglomerular apparatus and therefore participates in TGF signal transmission. In additional experiments we determined by frequency and timedomain analysis that renal autoregulation is significantly reduced in CD39deficient mice in both its myogenic and TGF components.[unreadable] 3. It is well established that renin synthesis and renin secretion are inversely related to salt intake with salt restriction causing stimulation and salt loading causing inhibition of the renin system. The mechanisms responsible for this effect of salt are not entirely clear. In the present experiments we assessed the role of beta-adrenergic receptors in salt-dependent regulation of renin release by determining the effect of salt intake on basal and furosemidestimulated renin release in conscious wild type and beta1beta2-adrenergic (beta-ADR) receptor-deficient mice (2). Plasma renin concentration (PRC) in tail vein blood was taken as index of renin release. On a control diet, PRC (ng AngIml hr) was significantly higher in WT than ADR mice (1338 vs. 304; p<04). PRC of mice kept on a low Na diet (.003%) for one week was increased in both WT and betaADR mice (to 2789 and 73354 respectively). Similarly, a high Na diet (8%) suppressed PRC in both genotypes (to 676 in WT, and to 85 in beta-ADR mice). Furosemide increased PRC in both WT and betaADR mice (to 7084 and to 3277 respectively). The increment of PRC caused by furosemide was augmented by a low Na diet and diminished by a high Na diet in both WT and beta-ADR mice. Mean arterial blood pressure measured by radiotelemetry was lower in beta-ADR than WT mice (93 vs. 106 mm Hg), but it was not altered by salt intake in either betaADR or WT mice. We conclude from these data that renin synthesis and release under basal conditions is markedly dependent upon the presence of adrenergic receptors, but that the modulating effect of salt intake on renin expression and secretion is maintained in the absence of adrenergic receptors. Thus, the regulation of renin release by salt diet is dominated by regulatory inputs other than the sympathetic nervous system.[unreadable] 4. In an extensive collaborative effort we have studied the role of adenosine 1 receptors (A1AR) in various organ systems of the body. Organism-wide actions of adenosine are strongly suggested by the multiplicity of effects, including effects on blood pressure, exerted by the adenosine receptor antagonist caffeine. Fluid intake was elevated in the absence of A1AR and non-responsive to caffeine suggesting that A1AR activation reduces fluid intake (4). In the cardiovascular system A1AR were found to enhance the ischemic tolerance of the heart (13,16,17). In the central nervous system, A1AR deficiency caused a dramatic worsening of an experimental traumatic brain injury revealing an important anticonvulsant action of A1AR in brain trauma (12). Furthermore, A1AR expressed in microglial cells attenuate the growth of experimental glioblastoma (8).